Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.
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PMID:Vascular hypertrophy in hypertension: role of the renin-angiotensin system. 952 May 14

The Ca2+-sensing receptor protein and the Ca2+-inhibitable type 6 adenylyl cyclase mRNA are present in a defined segment of the rat renal tubule leading to the hypothesis of their possible functional co-expression in a same cell and thus to a possible inhibition of cAMP content by extracellular Ca2+. By using microdissected segments, we compared the properties of regulation of extracellular Ca2+-mediated activation of Ca2+ receptor to those elicited by prostaglandin E2 and angiotensin II. The three agents inhibited a common pool of hormone-stimulated cAMP content by different mechanisms as follows. (i) Extracellular Ca2+, coupled to phospholipase C activation via a pertussis toxin-insensitive G protein, induced a dose-dependent inhibition of cAMP content (1.25 mM Ca2+ eliciting 50% inhibition) resulting from both stimulation of cAMP hydrolysis and inhibition of cAMP synthesis; this latter effect was mediated by capacitive Ca2+ influx as well as release of intracellular Ca2+. (ii) Angiotensin II, coupled to the same transduction pathway, also decreased cAMP content; however, its inhibitory effect on cAMP was mainly accounted for by an increase of cAMP hydrolysis, although angiotensin II and extracellular Ca2+ can induce comparable release of intracellular Ca2+. (iii) Prostaglandin E2, coupled to pertussis toxin-sensitive G protein, inhibited the same pool of adenylyl cyclase units as extracellular Ca2+ but by a different mechanism. The functional properties of the adenylyl cyclase were similar to those described for type 6. The results establish that the co-expression of a Ca2+-inhibitable adenylyl cyclase and of a Ca2+-sensing receptor in a same cell allows an inhibition of cAMP accumulation by physiological concentrations of extracellular Ca2+.
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PMID:Co-expression of a Ca2+-inhibitable adenylyl cyclase and of a Ca2+-sensing receptor in the cortical thick ascending limb cell of the rat kidney. Inhibition of hormone-dependent cAMP accumulation by extracellular Ca2+. 961 33

AT1 receptor is responsible for most of the physiological effects of Angiotensin II (Ang II). AT1 receptor belongs to the G-protein-coupled receptor (GPCR) family, and it mediates its actions through the coupling of the Gq/11 protein with phospholipase C beta. Classical pharmacology has used the sensitivity of GPCR ligands to uncoupling agents as a criteria to discriminate agonists (which are sensitive) from antagonists (which are insensitive). In this study, the uncoupling agents GTP gamma S and pentosan sulfate (PS) (a low molecular weight polyanion) were used to further characterize the molecular interactions between Ang II analogs and the AT1 receptor. We show that some Ang II antagonists are sensitive to the conformational change of the AT1 receptor induced by uncoupling agents. These results demonstrate that there is no direct relationship between the intrinsic activity of a ligand and its affinity for different conformations of the AT1 receptor and that the sensitivity of GPCR ligands to uncoupling agents can not be used as a criteria to discriminate agonists from antagonists.
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PMID:Effect of uncoupling agents on AT1 receptor affinity for antagonist analogs of angiotensin II. 966 23

Angiotensin II (AngII), a circulating vasoactive peptide, interacts with specific membrane-bound receptors on the target tissues (vessels, kidneys and adrenal gland). Using new pharmacological tools and molecular cloning, these receptors have been classified in two types, called AT1 et AT2, whereas two subtypes, called AT1A et AT1B, have been identified for the rodent AT1 receptors, but not in humans. All these receptors present a seven hydrophobic transmembrane domain structure, which is classical for G protein coupled receptors. The interspecies molecular homology of these AngII receptors is high (> 90 per cent identity) within the same type of receptor, but is rather low (approximately 35 per cent identity) between the two types of receptors. The AT1 receptors are responsible for most of the AngII physiological actions and are coupled to a Gq protein, which activates a phospholipase C producing second messengers which activate protein kinases C and mobilize calcium intracellular stores. More recently, a strong interaction of this receptor has been demonstrated with the signalling pathways of the tyrosine kinases. The molecular mechanisms and the physiological importance of these interactions remain to be elucidated. The intracellular signalling (Gi coupling and tyrosine phosphatase activation) and the physiological actions (cellular differentiation, apoptosis) of the AT2 receptors are more controversial.
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PMID:[Angiotensin II receptors: classification, structure, and signal transduction]. 977 19

Angiotensin II (Ang II) receptors are 7 transmembrane domain receptors corresponding to 2 pharmacologically and molecularly distinct receptors, called AT1 and AT2, the primary structures of which have been established by molecular cloning. Most if not all the physiological actions of Ang II are mediated by the AT1 receptor, which is coupled to a Gq protein activating a phospholipase C (PLC), which in turn mobilizes the intracellular calcium stores and activates protein kinases C. Many site directed mutagenesis works have allowed to identify short extracellular sequences responsible for the Ang II binding, whereas non-peptidic AT1-specific antagonists bind to a different transmembranar site. Structural modifications are responsible for the change of the receptor from an inactive to an active state. At the basal state, the receptor is mostly in an inactive state; agonists present a better affinity for the active state, displacing the equilibrium to this state; at the opposite, the inverse agonists present a better affinity for the inactive state. Antagonists present a similar affinity for both states of the receptor. Several mutations of polar residues of the transmembrane domains block the receptor either in an inactive state (D74D, S115A, Y292F) or in a constitutively active state (N111A and N295A). After activation, the receptor is coupled to different intracellular proteins, the first of them being the G proteins of the Gq/11 family. The sequences of the receptor involved in this coupling correspond to the 2nd, the 3rd intracellular loops and the proximal segment of the carboxyterminal domain. Other sequences interact with other proteins, such as the 319YIPP332 sequence of the carboxyterminus, which interacts with the Jak2 tyrosine kinase. After the binding of a peptidic ligands, the ligand-receptor complex is internalized independently for the G protein coupling. Again, site directed mutagenesis experiments have localized a sequence of the carboxyterminus (329STLSTKMSTLS338) involved in the internalization. This serine and threonine-rich sequence plays also a role in the desensitization of the AT1 receptor, consecutively to its phosphorylation. The AT2 receptor is only 34% identical to the AT1 receptor and its functions are far less understood. Its physiological functions (apoptosis and antiproliferative actions) and its signaling pathways (activation of Gi proteins and tyrosine phosphatases) are still a matter of debate.
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PMID:[Molecular structure and function of angiotensin ii receptors]. 985 75

Angiotensin II (Ang II) receptors of the AT1 subtype are coupled to heterotrimeric G nucleotide-binding proteins, G(q/11), to activate phospholipase C-beta isoforms with production of inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol. The resultant release of intracellular Ca2+ and increased Ca2+ influx are major determinants of several acute cellular responses initiated by Ang II, including secretion of aldosterone from the adrenal cortex and smooth muscle contraction. However, cellular events related to more prolonged effects of Ang II, such as hypertrophic and hyperplastic responses, are triggered by intracellular signaling cascades that are less dependent on Ca2+ signals. The Ang II-induced activation of Raf-1 kinase, p42 MAP-kinase and c-fos expression in response to Ang II in adrenal glomerulosa cells does not require Ca2+ influx. Moreover, the dose-response relationships for Raf-1 activation, MAP-kinase activation and mitogenesis show significantly higher sensitivity to Ang II than the InsP3, Ca2+-release and aldosterone secretory responses. The sensitivities of both Raf-1 kinase and MAP-kinase stimulation by Ang II to the inhibitors of phosphoinositide kinases, wortmannin and LY 294002, suggest that inositol phospholipids may play a role in these activation events unrelated to their role in Ca2+ signaling. To investigate the changes of various inositides after stimulation at the single cell level, fluorescent probes were developed in which pleckstrin homology domains with distinct binding specificities to inositol phospholipids were fused to the green fluorescent protein and expressed in NIH 3T3 cells. The use of these probes revealed heterogeneity of the inositol lipid pools and their complex relationship to Ca2+ signals. The use of these tools will help to further clarify the complex role of these lipids in initiating Ca2+-dependent and -independent signaling responses.
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PMID:Signaling events activated by angiotensin II receptors: what goes before and after the calcium signals. 988 5

ACTH, Angiotensin II (Ang II) and Vasopressin (AVP) are among the well known regulators of aldosterone secretion and also have a trophic action on the adrenal gland. According to classic studies, Ang II and AVP activate phospholipase C (PLC), diacylglycerol (DAG) and inositol phosphate (InsPs) production whereas ACTH activates cAMP production. However, our data indicate that the three peptides are able to induce a time-dependent increase in the level of Tyr-phosphorylation of several proteins. Western Blot analysis indicates a biphasic activation of Tyr-phosphorylation by AVP, with a peak at 30 s and a second one at 15 min incubation. Ang II induced a rapid (2 min) and sustained activation of Tyr-phosphorylation, while ACTH induced a progressive time course with a plateau reached at 15 min. Ang II and AVP also increased phosphorylation of p42mapk and p44mapk, while ACTH did not affect MAPK activity. Moreover, pre-incubation of the cells with genistein (Tyr-kinase inhibitor) and PD 098059 (a MAPK inhibitor) did not affect InsPs production or aldosterone secretion induced by Ang II or AVP. These results suggest that the MAPK pathway is involved in the control of cell growth rather than aldosterone secretion.
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PMID:Involvement of tyrosine phosphorylation and MAPK activation in the mechanism of action of ACTH, angiotensin II and vasopressin. 988 17

Angiotensin II (AngII) is coupled to several important intracellular signaling pathways, and increases intracellular Ca2+. In vascular smooth muscle (VSM) cells, AngII is known to activate enzymes such as tyrosine protein kinase (Tyr-PK), phospholipase C (PLC), protein kinase C (PKC), and phophatidylinositol-3-kinase (PI-3-K). A non-receptor Tyr-PK, pp60(c-src), and PKC have been reported to stimulate the Ca2+ channels in VSM cells. However, less is known about AngII action on the voltage-gated Ca2+ channels. The Ca2+-channel currents of a cultured rat aortic smooth muscle cell line, A7r5, were recorded using whole-cell voltage clamp. Application of 50 nM AngII significantly increased the amplitude of Ba2+ currents through the voltage-gated Ca2+ channels (IBa) by 34. 5+/-9.1% (n=10) within 1 min. In the presence of lavendustin-A (5 microM), a selective inhibitor of Tyr-PK, AngII failed to stimulate IBa (n=5). AngII stimulation of IBa was also prevented by (5 microM) LY-294002, an inhibitor of PI-3-K (n=5). In contrast, H-7 (30 microM), an inhibitor of PKC, did not prevent the effect of AngII on IBa (n=6). These results suggest that AngII may stimulate the Ca2+ channels of VSM cells through Tyr-PK and PI-3-K under conditions that probably exclude participation of PK-C.
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PMID:Angiotensin II stimulation of Ca2+-channel current in vascular smooth muscle cells is inhibited by lavendustin-A and LY-294002. 991 87

Angiotensin II (Ang II) receptor subtypes AT1 and AT2 share 34% overall homology, but the least homology is in their third intracellular loop (3rd ICL). In an attempt to elucidate the role of the 3rd ICL in determining the similarities and differences in the functions of the AT1 and the AT2 receptors, we generated a chimeric receptor in which the 3rd ICL of the AT2 receptor was replaced with that of the AT1 receptor. Ligand-binding properties and signaling properties of this receptor were assayed by expressing this receptor in Xenopus oocytes. Ligand-binding studies using [125I-Sar1-Ile8] Ang II, a peptidic ligand that binds both the AT1 and the AT2 receptor subtypes, and 125I-CGP42112A, a peptidic ligand that is specific for the AT2 receptor, showed that the chimeric receptor has lost affinity to both ligands. However, IP3 levels of the oocytes expressing the chimeric receptor were comparable to the IP3 levels of the oocytes expressing the AT1 receptor, suggesting that the chimeric receptors could couple to phospholipase C pathway in response to Ang II. We have shown previously that the nature of the amino acid present in the position 215 located in the fifth transmembrane domain (TMD) of the AT2 receptor plays an important role in determining its affinity to different ligands. Our results from the ligand-binding studies of the chimeric receptor further support the idea that the structural organization of the region spanning the 5th TMD and the 3rd ICL of the AT2 receptor has an important role in determining the ligand-binding properties of this receptor.
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PMID:Role of the third intracellular loop of the angiotensin II receptor subtype AT2 in ligand-receptor interaction. 1006 67

The purpose of this study was to characterize the nature and mechanisms of angiotensin II-evoked calcium signaling in AR42J cells. Cytosolic calcium concentrations were determined using fura-2-based microfluorimetry. Angiotensin II causes elevations in free cytosolic calcium ([Ca2+]i) in the rat pancreatic acinar cell line AR42J. The mechanisms of angiotensin II-evoked calcium signaling were examined using fura-2-based fluorescent digital microscopy. Angiotensin II caused dose-dependent increments in [Ca2+]i over a concentration range of 0.1-1,000 nM, with an average increment of 243 +/- 16 nM at an angiotensin II concentration of 1,000 nM. Dup753, an AT1-specific antagonist, inhibited angiotensin II-evoked signaling, whereas the AT2 antagonist PD123,319 had no effect. Preincubation with the phospholipase C inhibitor U73122 reduced the response in [Ca2+]i to 25% of that of the control. Thapsigargin abolished angiotensin II-evoked calcium signaling. The inositol 1,4,5-trisphosphate receptor antagonist heparin introduced by radiofrequency electroporation inhibited responses to 46 +/- 6% of controls. Angiotensin II-evoked signals were reduced in magnitude and duration by elimination of Ca2+ from the extracellular buffer. Preincubation with pertussis toxin (100 ng/ml) had no effect. Angiotensin II did not stimulate cyclic AMP or suppress vasoactive intestinal peptide stimulated cyclic AMP production over the concentration range that caused Ca2+ signaling.
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PMID:Calcium signaling induced by angiotensin II in the pancreatic acinar cell line AR42J. 1009 Apr 17


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